Excessive bone loss occurs following spinal cord injury (SCI) leading to osteoporosis and an increased risk of fracture. While the underlying cause of this bone loss remains to be clarified, it is distinct in severity and pattern from other known causes of osteoporosis including disuse and postmenopausal osteoporosis. Currently, little is known about the cause of this bone loss or the natural history and specific factors that contribute to its severity. Based on preliminary studies, we hypothesize the osteoprotective marker osteoprotegerin (OPG) is involved in the pathogenesis of SCI-induced bone loss and may be a biomarker of disease severity and fracture risk in this population. Furthermore, if confirmed, OPG is a potentially powerful therapeutic target in the prevention and treatment of neurogenic bone loss. In this exploratory and developmental program, we propose to investigate differences in bone mineral density in individuals with tetraplegia and in those with lesser degrees of SCI. We will determine the relationship between bone mineral density at sites below the neurological lesion and circulating levels of OPG. Participants with SCI whose health behaviors (smoking, alcohol use) and comorbid illnesses are known due to enrollment in a longitudinal health study at VA Boston will be studied. As osteoporosis is prevalent in this patient population but currently under-treated, we expect to contribute to the understanding of this disease process for the development of improved clinical interventions. Furthermore, this work will contribute to the understanding of bone loss following neurological injury and will have broader health implications for health conditions ranging from stroke to cerebral palsy. PUBLIC HEALTH RELEVANCE: This project seeks to understand bone loss triggered by spinal cord injury. A rapid, severe bone loss occurs after the spinal cord injury leaving the bones brittle and easy to fracture. This bone loss is not well understood. But, it appears to be different from bone loss seen with aging in that it affects the knees more than the hips and spine. We believe the degree of paralysis is the most important factor in determining how much bone is lost following spinal cord injury. We will test this hypothesis by determining bone density in subjects with more severe injury and those with less severe injury. We will also test the hypothesis that neurological injury causes a deficiency of a molecule in the blood known to protect bone density. We believe individuals with the most severe form of paralysis will have lower levels of this molecule (osteoprotegerin or OPG) and lower bone mineral density.